Obesity, generally defined as a body mass index (BMI) of more than 30 kilogram per square meter (Kg/m2), is a major health problem throughout the world. It is a risk factor for hypertension, diabetes and cardiovascular disease. Obesity is viewed as an energy storage disorder, resulting when energy input exceeds energy output. Most of the excess calories are stored as fat (more than 95% of fat is triglyceride) in the adipose tissue leading to obesity, and when stored in non-adipose tissue it leads to insulin resistance. Hence, inhibition of triglyceride synthesis represents a potential therapeutic strategy for human obesity and type 2 diabetes.
Metabolic syndrome, also known as Syndrome-X, is characterized by increased body weight, altered glucose homeostasis with insulin resistance, elevated plasma triglyceride levels and low-density lipoprotein-cholesterol, high blood pressure, and increased risk of cardiovascular morbidity and mortality. The prevalence of metabolic syndrome has risen dramatically in the US and rest of the world. In the US, metabolic syndrome affects roughly 25% of adults over the age of 20 years and up to 45% of the population over the age of 50 years (JAMA, 287, 356-359 (2002). The currently available therapies for addressing the disorders associated with metabolic syndrome are far from satisfactory.
A key enzyme in the synthesis of triglycerides is acylCoA: diacylglycerol acyltransferase (DGAT). Genes for two DGAT enzymes, DGAT1 and DGAT2 have been identified. Both DGAT1 and DGAT2 are highly expressed in tissues that are active in triglyceride synthesis such as white adipose tissue (WAT), intestine, liver, skeletal muscle and mammary gland (Proc. Natl. Acad. Sciences U.S.A, 95, 13018-13023 (1998); J. Biol. Chem., 276, 38870-38876 (2001)).
Studies in experimental animals suggest that inhibiting or reducing the activity of the DGAT1 enzyme results in resistance to the development of obesity, diabetes and associated complications. DGAT1 knockout studies in mice have shown that these mice are viable and resistant to obesity (Nat. Genet., 25, 87-90 (2000)), whereas DGAT2 knockout mice die soon after birth as there is no stored form of energy source due to lack of adipose tissues (J. Biol. Chem. 279, 11767-11776 (2004)). In contrast to DGAT2 knockout mice, DGAT1 knockout mice are viable and are resistant to diet-induced obesity and steatosis. In addition, these mice are more sensitive to insulin and leptin (J. Clin. Invest. 109, 1049-1055 (2002)). Heterozygous DGAT1 knockout mice are also resistant to obesity (Thromb. Vasc. Biol., 25, 482-486 (2005); Nutr. Metab (Lond.), 3, 10 (2006)). These studies together suggest that DGAT2 plays a fundamental role in triglyceride synthesis and is essential for survival, whereas DGAT1 contributes to triglyceride synthesis and plays an important role in regulating energy metabolism.
Additional studies with DGAT1 antisense oligonucleotides indicate that inhibition of DGAT1 results in decrease in blood glucose in ob/ob mice. Thus, resistance to obesity due to increased energy expenditure and reduced energy absorption along with an apparent improvement in insulin sensitivity associated with DGAT1 deficiency suggests that inhibition of DGAT1 could be a potential treatment strategy for addressing metabolic syndrome.
Hence, there has been an increased urge among pharmaceutical companies to develop novel therapies for treating metabolic disorders associated with syndrome-X. One target that has received much attention for treatment of metabolic syndrome is the DGAT1 enzyme (Trends Cardiovasc. Medicine, 10, 188-192 (2000); Curr. Drug Targets Immune Endocr. Metabol. Disorders, 3, 263-270 (2003)).
The following patent publications describe compounds that inhibit DGAT1 activity: WO2004/100881 and WO2006/044775 describe biphenyl-4-yl-carbonyl amino acid derivatives, WO2004/047755 describes fused bicyclic nitrogen-containing heterocycles, WO2006/019020 describes substituted ureas, WO2007/016538 describes biphenyl sulfonamides, WO2006/082952 describes amide derivatives, WO2006/134317 describes oxadiazole derivatives and WO2006/019020 describes substituted ureas.
US2004/0224997 and WO2006/113919 describe aryl alkyl acid, and JP2004-67635 describes thiazoleamido substituted phenyl compounds.
WO1995/014683 describes isoxazoline and isoxazole derivatives as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex for the treatment of thromboembolic disorders.
WO2007/024922 describes nitrogen containing heteroaryl compounds as immunosuppressant useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions.